The high molecular weight melanoma-associated antigen (HMW-MAA) is a 450 kD chondroitin sulfate proteoglycan with a 250 kD core glycoprotein. HMW-MAA consists of a large extracellular domain which contains fifteen potential N-linked glycosylation sites, a hydrophobic transmembrane region and a short cytoplasmic tail of seventy-five amino acids which contains a potential protein kinase C phosphorylation site. This antigen, also known as chondroitin sulfate proteoglycan 4 (CSPG4) and melanoma-associated chondroitin sulfate proteoglycan (MCSP), belongs to a family of adhesion receptors that mediate both cell-cell and cell-extracellular matrix interactions (Chekenya et al. (1999) Int J Dev Neurosci 17:421-35).
HMW-MAA is not expressed on normal human tissues except for nevus cells, pericytes and vascular endothelial cells. The expression of HMW-MAA on vascular endothelial cells suggests a possible role in angiogenesis. Notably, HMW-MAA is expressed on the majority of melanoma cells and on the surface of hematopoeitic progenitor cells in acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML) (Campoli et al. (2004) Crit Rev Immunol 24:267-96) as well as on basal cell carcinoma cells (Kageshita (1985) J. Invest. Dermatol. 85: 535-37). HWM-MAA may be shed from a cell and is detectable in the sera of both melanoma patients and normal individuals.
Several lines of evidence suggest that HMW-MAA plays important roles in intracellular signal cascades important for cellular adhesion, spreading, and invasion. These include the activation of small Rho family GTPase Cdc42 and of the adaptor protein p130cas, as well as the association of HMW-MAA with membrane-type 3 matrix metalloproteinase on melanoma cells (Eisenmann at al. (1999) Nat Cell Biol 1:507-13; Iida et al. (2001) J. Biol Chem 276:18786-94). Furthermore, elevated HMW-MAA expression in early tumors has been proposed to facilitate tumor progression by enhancing the activation of focal adhesion kinase (FAK) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) (Yang et al. (2004) J Cell Biol 165:881-91), Accordingly, HMW-MAA may be a target in the treatment of cancer.